@article {294, title = {Structural changes of vitamin D receptor induced by 20-epi-1alpha,25-(OH)2D3: an insight from a computational analysis}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {113}, year = {2009}, month = {2009 Feb}, pages = {253-8}, abstract = {We employ a new computational tool CCOMP for the comparison of side chain (SC) conformations between crystal structures of homologous protein complexes. The program is applied to the vitamin D receptor (VDR) liganded with 1alpha,25-(OH)(2)D(3) (in 1DB1) or its 20-epi (in 1IE9) analog with an inverted C-20 configuration. This modification yields no detectable changes in the backbone configuration or ligand topology in the receptor binding cavity, yet it dramatically increases transcription, differentiation and antiproliferation activity of the VDR. We applied very stringent criteria during the comparison process. To eliminate errors arising from the different packing of investigated crystals and the thermal flexibility of atoms, we studied complexes belonging to the same space group, having a low R value (0.2) and a B-factor below 40 for compared residues. We find that 20-epi-1alpha,25-(OH)(2)D(3) changes side chain conformation of amino acids residing far away from direct ligand-VDR contacts. We further verify that a number of the reoriented residues were identified in mutational experiments as important for interaction with SRC-1, GRIP, TAFs co-activators and VDR-RXR heterodimerization. Thus, CCOMP analysis of protein complexes may be used for identifying amino acids that could serve as targets for genetic engineering, such as mutagenesis.}, keywords = {Animals, Bone Density Conservation Agents, Calcitriol, Computer Simulation, Crystallography, X-Ray, Drug Design, Humans, Ligands, Molecular Structure, Protein Structure, Tertiary, Receptors, Calcitriol, Reproducibility of Results, Software, Transcription, Genetic}, issn = {1879-1220}, doi = {10.1016/j.jsbmb.2009.01.007}, author = {Wanda Sicinska and Piotr Rotkiewicz} } @article {254, title = {Clustering as a supporting tool for structural drug design}, journal = {Acta Poloniae Pharmaceutica. Drug Research}, volume = {63}, year = {2006}, month = {2006 Sep-Oct}, pages = {436-8}, keywords = {Cluster Analysis, Computer Simulation, Drug Design, Ligands, Models, Molecular, Molecular Structure, Protein Binding}, issn = {0001-6837}, author = {Dominik Gront and Mateusz Kurcinski and Andrzej Koli{\'n}ski} } @article {Hoffmann2006, title = {Three dimensional model of severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain and molecular design of severe acute respiratory syndrome coronavirus helicase inhibitors}, journal = {Journal of Computer-Aided Molecular Design}, volume = {20}, number = {5}, year = {2006}, month = {may}, pages = {305{\textendash}319}, abstract = {The modeling of the severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain was performed using the protein structure prediction Meta Server and the 3D Jury method for model selection, which resulted in the identification of 1JPR, 1UAA and 1W36 PDB structures as suitable templates for creating a full atom 3D model. This model was further utilized to design small molecules that are expected to block an ATPase catalytic pocket thus inhibit the enzymatic activity. Binding sites for various functional groups were identified in a series of molecular dynamics calculation. Their positions in the catalytic pocket were used as constraints in the Cambridge structural database search for molecules having the pharmacophores that interacted most strongly with the enzyme in a desired position. The subsequent MD simulations followed by calculations of binding energies of the designed molecules were compared to ATP identifying the most successful candidates, for likely inhibitors - molecules possessing two phosphonic acid moieties at distal ends of the molecule.}, keywords = {Amino Acid Sequence, Catalytic Domain, Conserved Sequence, DNA Helicases, DNA Helicases: antagonists \& inhibitors, DNA Helicases: chemistry, Drug Design, Enzyme Inhibitors, Enzyme Inhibitors: pharmacology, Models, Molecular, Molecular Sequence Data, Protein, SARS Virus, SARS Virus: enzymology, Sequence Alignment, Structural Homology, Thermodynamics}, issn = {0920-654X}, doi = {10.1007/s10822-006-9057-z}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16972168}, author = {Marcin Hoffmann and Krystian Eitner and Marcin von Grotthuss and Leszek Rychlewski and Ewa Banachowicz and Tomasz Grabarkiewicz and Tomasz Szkoda and Andrzej Koli{\'n}ski} } @article {Sikorski2000, title = {Computer simulations of the properties of the alpha2, alpha2C, and alpha2D de novo designed helical proteins}, journal = {Proteins}, volume = {38}, number = {1}, year = {2000}, month = {jan}, pages = {17{\textendash}28}, abstract = {Reduced lattice models of the three de novo designed helical proteins alpha2, alpha2C, and alpha2D were studied. Low temperature stable folds were obtained for all three proteins. In all cases, the lowest energy folds were four-helix bundles. The folding pathway is qualitatively the same for all proteins studied. The energies of various topologies are similar, especially for the alpha2 polypeptide. The simulated crossover from molten globule to native-like behavior is very similar to that seen in experimental studies. Simulations on a reduced protein model reproduce most of the experimental properties of the alpha2, alpha2C, and alpha2D proteins. Stable four-helix bundle structures were obtained, with increasing native-like behavior on-going from alpha2 to alpha2D that mimics experiment.}, keywords = {Amino Acid Sequence, Computer Simulation, Drug Design, Molecular Sequence Data, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Secondary, Thermodynamics}, issn = {0887-3585}, url = {http://www.ncbi.nlm.nih.gov/pubmed/10651035}, author = {Andrzej Sikorski and Andrzej Koli{\'n}ski and Jeffrey Skolnick} } @article {Sikorski1998, title = {Computer simulations of de novo designed helical proteins}, journal = {Biophysical Journal}, volume = {75}, number = {1}, year = {1998}, month = {jul}, pages = {92{\textendash}105}, abstract = {In the context of reduced protein models, Monte Carlo simulations of three de novo designed helical proteins (four-member helical bundle) were performed. At low temperatures, for all proteins under consideration, protein-like folds having different topologies were obtained from random starting conformations. These simulations are consistent with experimental evidence indicating that these de novo designed proteins have the features of a molten globule state. The results of Monte Carlo simulations suggest that these molecules adopt four-helix bundle topologies. They also give insight into the possible mechanism of folding and association, which occurs in these simulations by on-site assembly of the helices. The low-temperature conformations of all three sequences have the features of a molten globule state.}, keywords = {Amino Acid Sequence, Biophysical Phenomena, Biophysics, Computer Simulation, Dimerization, Drug Design, Hydrogen Bonding, Models, Molecular, Molecular Sequence Data, Monte Carlo Method, Protein Conformation, Protein Folding, Protein Structure, Proteins, Proteins: chemistry, Secondary, Thermodynamics}, issn = {0006-3495}, doi = {10.1016/S0006-3495(98)77497-1}, url = {http://www.ncbi.nlm.nih.gov/pubmed/10651035}, author = {Andrzej Sikorski and Andrzej Koli{\'n}ski and Jeffrey Skolnick} }